1. Field of the Invention
The present invention relates to a process for producing an optically active compound.
2. Discussion of the Background
3-(1-Amino-1,3-dicarboxy-3-hydroxy-butan-4-yl)-indole (hereinafter referred to as “monatin”) is contained in the root of Scherochitoma ilicifolius, and its sweetness is several hundred times as high as sucrose. Thus this compound is expected to be a low calorie sweetener (see, JP Patent Kokai Publication No. JP-A-64-25757).

In this specification, the term “monatin” is used as the generic designation for the four types of stereoisomers without being limited to the (2S,4S)-isomer. Thus, the designation of “monatin” means at least one of (2S,4S)-, (2S,4R)-, (2R,4S)- and (2R,4R)-isomers of monatin, except in the a case when it is used for limiting to a particular isomer.
For the synthesis of monatin, nine cases have been reported:
(1) the method as described in Organic Letters, vol. 2, no. 19, pp. 2967-2970 (2000);
(2) the method as disclosed in U.S. Pat. No. 5,994,559;
(3) the method as described in Synthetic Communication, vol. 24, no. 22, pp. 3197-3211 (1994);
(4) the method as described in Synthetic Communication, vol. 23, no. 18, pp. 2511-2526 (1993);
(5) the method as described in Tetrahedron Letters, vol. 42, no. 39, pp. 6793-6796 (2001);
(6) the method as described in Japanese Patent Kokai Publication No. JP-P2002-060382A;
(7) the method as described in Japanese Patent Kokai Publication No. JP-P2004-331650A;
(8) the procedure as described in WO2004/067494A1; and
(9) the procedure as described in WO2003/059865A1.
Particularly, in the procedure as described in WO2003/059865A1, optically active monatin can be produced in a short process from pyruvic acid and indole-3-pyruvic acid, and so it is a commercially excellent process.
However, since the intermediate for production, i.e., 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid, is obtained as the racemate at the 4 position, it has to be resolved optically, and the undesired enantiomer at the 4 position has to be recycled. Therefore, an additional improvement has been required.
As an example of an improvement, an asymmetric cross aldol reaction utilizing an enzyme (aldolase) has been reported in, for example, WO2003/056026. According to these enzymatic procedures, a highly optically pure 4-hydroxy-4-(3-indolylmethyl)-2-ketoglutaric acid can be synthesized from pyruvic acid and indole-3-pyruvic acid even though in low yield.
So far, in the asymmetric cross aldol reaction using an α-keto acid ester as a donor and acceptor, it has been reported that the enantiomeric induction was achieved only in three cases. That is, the procedures are described in the following documents:
(1) The procedure as described in Organic & Biomolecular Chemistry, vol. 2, pp. 1077-1085 (2004);
(2) The procedure as described in Chemical Communications, pp. 2211-2212 (2000); and
(3) The procedure as described in Organic Letters, vol. 7, no. 21, pp. 4657-4660 (2005).
The methods as described in the above-mentioned documents, however, employed α-keto acid esters as donors in every cases, and accordingly cannot be applied to production of monatin in which a free α-keto acid, pyruvic acid, is used as a donor. In particular, in the procedure described in Chemical Communications, pp. 2211-2212 (2000) and Organic Letters, vol. 7, no. 21, pp. 4657-4660 (2005), only the dimerization of ethyl pyruvate is mentioned, but there is no description of the asymmetric cross aldol reaction using different pyruvic acids as donor and acceptor in the production of monatin. Organic & Biomolecular Chemistry, vol. 2, pp. 1077-1085 (2004) describes the asymmetric cross aldol reaction using different pyruvic acid esters. In this reaction, however, ethyl trifluoropyruvate as an α-keto acid ester is used as an acceptor which has no active hydrogen, and accordingly it cannot be applied to the production of monatin using indole-3-pyruvic acid as an acceptor which has an active hydrogen.
Thus, there is no report on an asymmetric catalyst which is capable of discriminating pyruvic acid and indole-3-pyruvic acid as a donor and an acceptor, respectively, which are required in production of monatin, indicating that it was difficult in view of the current level of technology. All of the raw materials have an active hydrogen at the α-position of the carbonyl group and can act as donor or acceptor; this makes it difficult to control the reaction site. This difficulty would easily be understood among the persons skilled in the art.
Thus, there remains a need for a process for selectively producing the enantiomer at the 4 position in the cross aldol reaction of pyruvic acid and indole-3-pyruvic acid.